rs3740281

Variant names:

• chr10-89012393-G-A
• rs3740281
• NM_000043.6:c.651+312G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000043.6(FAS):​c.651+312G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.124 in 310,070 control chromosomes in the GnomAD database, including 2,886 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.11 (1195 hom., cov: 32)
  • Exomes 𝑓: 0.14 (1691 hom.)
• Consequence: FAS NM_000043.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.222
• Publications: 1 publications found

Genes affected

FAS (HGNC:11920): (Fas cell surface death receptor) The protein encoded by this gene is a member of the TNF-receptor superfamily. This receptor contains a death domain. It has been shown to play a central role in the physiological regulation of programmed cell death, and has been implicated in the pathogenesis of various malignancies and diseases of the immune system. The interaction of this receptor with its ligand allows the formation of a death-inducing signaling complex that includes Fas-associated death domain protein (FADD), caspase 8, and caspase 10. The autoproteolytic processing of the caspases in the complex triggers a downstream caspase cascade, and leads to apoptosis. This receptor has been also shown to activate NF-kappaB, MAPK3/ERK1, and MAPK8/JNK, and is found to be involved in transducing the proliferating signals in normal diploid fibroblast and T cells. Several alternatively spliced transcript variants have been described, some of which are candidates for nonsense-mediated mRNA decay (NMD). The isoforms lacking the transmembrane domain may negatively regulate the apoptosis mediated by the full length isoform. [provided by RefSeq, Mar 2011]

FAS Gene-Disease associations (from GenCC):

• autoimmune lymphoproliferative syndrome

  Inheritance: AD, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• autoimmune lymphoproliferative syndrome type 1

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.156 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAS	NM_000043.6	c.651+312G>A		intron_variant	Intron 7 of 8	ENST00000652046.1	NP_000034.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAS	ENST00000652046.1	c.651+312G>A		intron_variant	Intron 7 of 8		NM_000043.6	ENSP00000498466.1

Frequencies

GnomAD3 genomes AF: 0.110 AC: 16759 AN: 151908 Hom.: 1198 Cov.: 32

Gnomad AFR AF: 0.0272

Gnomad AMI AF: 0.129

Gnomad AMR AF: 0.103

Gnomad ASJ AF: 0.138

Gnomad EAS AF: 0.00770

Gnomad SAS AF: 0.106

Gnomad FIN AF: 0.176

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.159

Gnomad OTH AF: 0.112

GnomAD4 exome AF: 0.137 AC: 21683 AN: 158046 Hom.: 1691 AF XY: 0.135 AC XY: 11617 AN XY: 85884

African (AFR) AF: 0.0308 AC: 136 AN: 4420

American (AMR) AF: 0.100 AC: 657 AN: 6538

Ashkenazi Jewish (ASJ) AF: 0.133 AC: 518 AN: 3886

East Asian (EAS) AF: 0.00538 AC: 37 AN: 6874

South Asian (SAS) AF: 0.113 AC: 3206 AN: 28360

European-Finnish (FIN) AF: 0.168 AC: 1125 AN: 6698

Middle Eastern (MID) AF: 0.125 AC: 70 AN: 562

European-Non Finnish (NFE) AF: 0.161 AC: 14884 AN: 92700

Other (OTH) AF: 0.131 AC: 1050 AN: 8008

GnomAD4 genome AF: 0.110 AC: 16747 AN: 152024 Hom.: 1195 Cov.: 32 AF XY: 0.108 AC XY: 8053 AN XY: 74298

African (AFR) AF: 0.0271 AC: 1125 AN: 41468

American (AMR) AF: 0.103 AC: 1576 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.138 AC: 478 AN: 3470

East Asian (EAS) AF: 0.00791 AC: 41 AN: 5182

South Asian (SAS) AF: 0.105 AC: 506 AN: 4806

European-Finnish (FIN) AF: 0.176 AC: 1858 AN: 10556

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.159 AC: 10777 AN: 67952

Other (OTH) AF: 0.111 AC: 234 AN: 2110

Alfa AF: 0.132 Hom.: 210

Bravo AF: 0.0999

Asia WGS AF: 0.0480 AC: 169 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	7.2
DANN	Benign	0.84
PhyloP100		-0.22
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3740281; hg19: chr10-90772150;